Natural resistance to a number of infectious disease organisms in mice is under genetic control. The nature of these genes and the immune mechanisms that they control are being investigated. Resistance to Rickettsia Tsusugomushi, the agent of scrub typhus, is controlled by a single, dominant gene (RIC) that is located in the middle of chromosome 5. This gene controls some function that is operative within four hours after bacterial infection. Resistance to Salmonella typhimurium, the agent of typhoid fever is controlled by three genes: 1) an x-linked gene that controls B cell differentiation (xio), 2) the LPS gene and 3) a chromosome 1 gene (Ity) that may control some aspect of cell mediated immunity. Resistance to Herpes simplex virus-1, the causative agent of acute gingivostomatitis and recurrent herpes labialis, is also polygenic. The number, location and mechanisms controlled by these genes are currently under investigation. Characterization of the genes that control resistance to infectious organisms will facilitate identification of individuals susceptible to any given disease and enable the development of appropriate preventive or therapeutic measures.